The long term goals of the proposal are to determine the extent to which modulation of the local injury site, combined with trophic factor support and neural tissue transplantation can lead to structural repair of the chronically injured spinal cord.
The specific aims address the hypothesis that combinations of experimental interventions in the chronic state after injury can promote axonal regeneration and integration across an injury site. It will also be determined whether progressive changes in chronically injured neurons influence their ability to respond to these interventive approaches and whether non-neuronal cells associated with the injury site modulate the neuronal response to injury and to trophic factor treatment.
Aim I will utilize an established SCI-peripheral nerve graft model to determine how treatments of the graft spinal cord interface with compounds that modulate the non-neuronal cell response to injury can effectively promote axonal growth beyond the PN graft, into the dorsal horn of the spinal cord.
The second aim will determine if a combination of neurotrophic factors and fetal tissue transplantation can increase axonal growth from a PN graft, into the spinal cord. Experiments for Aim III will determine why the regenerative effort of some neurons at different post injury intervals appears to be greater than that exhibited by other neurons. Neuronal survival, axonal retraction and changes in the expression of regeneration associated genes at various stages after spinal cord injury and in response to trophic factor treatment will be measured in relation to the regenerative response of specific brainstem neuron populations.
In aim I V, changes in the cellular and biochemical composition of nonneuronal cells at a chronic lesion site and after trophic factor treatment will be examined by immunocytochemical labeling and multiprobe ribonuclease protection assays. We will compare these changes with the regenerative effort of factor-treated neurons observed in the previous Aims to reach and understanding of the impact of non-neuronal cell responses on the ability to promote regeneration. Overall, these experiments will provide valuable information about cellular and molecular aspects of the neuronal and non-neuronal response to long term injury and will assist in the design of interventive therapies to repair the chronically injured spinal cord.
|Sandrow-Feinberg, Harra R; Houlé, John D (2015) Exercise after spinal cord injury as an agent for neuroprotection, regeneration and rehabilitation. Brain Res 1619:12-21|
|Detloff, Megan Ryan; Smith, Evan J; Quiros Molina, Daniel et al. (2014) Acute exercise prevents the development of neuropathic pain and the sprouting of non-peptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury. Exp Neurol 255:38-48|
|Detloff, Megan Ryan; Wade Jr, Rodel E; Houlé, John D (2013) Chronic at- and below-level pain after moderate unilateral cervical spinal cord contusion in rats. J Neurotrauma 30:884-90|
|Houle, John D; Cote, Marie-Pascale (2013) Axon regeneration and exercise-dependent plasticity after spinal cord injury. Ann N Y Acad Sci 1279:154-63|
|Tom, Veronica J; Sandrow-Feinberg, Harra R; Miller, Kassi et al. (2013) Exogenous BDNF enhances the integration of chronically injured axons that regenerate through a peripheral nerve grafted into a chondroitinase-treated spinal cord injury site. Exp Neurol 239:91-100|
|Liu, Ting; Houle, John D; Xu, Jinye et al. (2012) Nanofibrous collagen nerve conduits for spinal cord repair. Tissue Eng Part A 18:1057-66|
|Cote, Marie-Pascale; Amin, Arthi A; Tom, Veronica J et al. (2011) Peripheral nerve grafts support regeneration after spinal cord injury. Neurotherapeutics 8:294-303|
|Sandrow-Feinberg, Harra R; Zhukareva, Victoria; Santi, Lauren et al. (2010) PEGylated interferon-beta modulates the acute inflammatory response and recovery when combined with forced exercise following cervical spinal contusion injury. Exp Neurol 223:439-51|
|Houle, John D; Amin, Arthi; Cote, Marie-Pascale et al. (2009) Combining peripheral nerve grafting and matrix modulation to repair the injured rat spinal cord. J Vis Exp :|
|Tom, Veronica J; Kadakia, Rachel; Santi, Lauren et al. (2009) Administration of chondroitinase ABC rostral or caudal to a spinal cord injury site promotes anatomical but not functional plasticity. J Neurotrauma 26:2323-33|
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